Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2
Abstract Background Patients with the genetic disorder Niemann-Pick type C2 disease (NP-C2) suffer from lysosomal accumulation of cholesterol causing both systemic and severe neurological symptoms. In a murine NP-C2 model, otherwise successful intravenous Niemann-Pick C2 protein (NPC2) replacement t...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Fluids and Barriers of the CNS |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12987-025-00621-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832571404986351616 |
|---|---|
| author | Charlotte Laurfelt Munch Rasmussen Signe Frost Frederiksen Christian Würtz Heegaard Maj Schneider Thomsen Eva Hede Bartosz Laczek Jakob Körbelin Daniel Wüstner Louiza Bohn Thomsen Markus Schwaninger Ole N. Jensen Torben Moos Annette Burkhart |
| author_facet | Charlotte Laurfelt Munch Rasmussen Signe Frost Frederiksen Christian Würtz Heegaard Maj Schneider Thomsen Eva Hede Bartosz Laczek Jakob Körbelin Daniel Wüstner Louiza Bohn Thomsen Markus Schwaninger Ole N. Jensen Torben Moos Annette Burkhart |
| author_sort | Charlotte Laurfelt Munch Rasmussen |
| collection | DOAJ |
| description | Abstract Background Patients with the genetic disorder Niemann-Pick type C2 disease (NP-C2) suffer from lysosomal accumulation of cholesterol causing both systemic and severe neurological symptoms. In a murine NP-C2 model, otherwise successful intravenous Niemann-Pick C2 protein (NPC2) replacement therapy fails to alleviate progressive neurodegeneration as infused NPC2 cannot cross the blood–brain barrier (BBB). Genetic modification of brain endothelial cells (BECs) is thought to enable secretion of recombinant proteins thereby overcoming the restrictions of the BBB. We hypothesized that an adeno-associated virus (AAV-BR1) encoding the Npc2 gene could cure neurological symptoms in Npc2−/− mice through transduction of BECs, and possibly neurons via viral passage across the BBB. Methods Six weeks old Npc2−/− mice were intravenously injected with the AAV-BR1-NPC2 vector. Composite phenotype scores and behavioral tests were assessed for the following 6 weeks and visually documented. Post-mortem analyses included gene expression analyses, verification of neurodegeneration in Purkinje cells, determination of NPC2 transduction in the CNS, assessment of gliosis, quantification of gangliosides, and co-detection of cholesterol with NPC2 in degenerating neurons. Results Treatment with the AAV-BR1-NPC2 vector improved motor functions, reduced neocortical inflammation, and preserved Purkinje cells in most of the mice, referred to as high responders. The vector exerted tropism for BECs and neurons resulting in a widespread NPC2 distribution in the brain with a concomitant reduction of cholesterol in adjacent neurons, presumably not transduced by the vector. Mass spectrometry imaging revealed distinct lipid alterations in the brains of Npc2−/− mice, with increased GM2 and GM3 ganglioside accumulation in the cerebellum and hippocampus. AAV-BR1-NPC2 treatment partially normalized these ganglioside distributions in high responders, including restoration of lipid profiles towards those of Npc2+/+ controls. Conclusion The data suggests cross-correcting gene therapy to the brain via delivery of NPC2 from BECs and neurons. |
| format | Article |
| id | doaj-art-ca5ae06a4b2d496fb72b7263e6159220 |
| institution | Kabale University |
| issn | 2045-8118 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj-art-ca5ae06a4b2d496fb72b7263e61592202025-02-02T12:37:36ZengBMCFluids and Barriers of the CNS2045-81182025-01-0122112810.1186/s12987-025-00621-4Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2Charlotte Laurfelt Munch Rasmussen0Signe Frost Frederiksen1Christian Würtz Heegaard2Maj Schneider Thomsen3Eva Hede4Bartosz Laczek5Jakob Körbelin6Daniel Wüstner7Louiza Bohn Thomsen8Markus Schwaninger9Ole N. Jensen10Torben Moos11Annette Burkhart12Neurobiology Research and Drug Delivery, Department of Health Science and Technology, Aalborg UniversityDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkDepartment of Molecular Biology and Genetics, Aarhus UniversityNeurobiology Research and Drug Delivery, Department of Health Science and Technology, Aalborg UniversityNeurobiology Research and Drug Delivery, Department of Health Science and Technology, Aalborg UniversityNeurobiology Research and Drug Delivery, Department of Health Science and Technology, Aalborg UniversityDepartment of Oncology, Hematology, and Bone Marrow Transplantation, University of Medical Center Hamburg-EppendorfDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkNeurobiology Research and Drug Delivery, Department of Health Science and Technology, Aalborg UniversityInstitute of Experimental and Clinical Pharmacology and Toxicology, University of LübeckDepartment of Biochemistry and Molecular Biology, University of Southern DenmarkNeurobiology Research and Drug Delivery, Department of Health Science and Technology, Aalborg UniversityNeurobiology Research and Drug Delivery, Department of Health Science and Technology, Aalborg UniversityAbstract Background Patients with the genetic disorder Niemann-Pick type C2 disease (NP-C2) suffer from lysosomal accumulation of cholesterol causing both systemic and severe neurological symptoms. In a murine NP-C2 model, otherwise successful intravenous Niemann-Pick C2 protein (NPC2) replacement therapy fails to alleviate progressive neurodegeneration as infused NPC2 cannot cross the blood–brain barrier (BBB). Genetic modification of brain endothelial cells (BECs) is thought to enable secretion of recombinant proteins thereby overcoming the restrictions of the BBB. We hypothesized that an adeno-associated virus (AAV-BR1) encoding the Npc2 gene could cure neurological symptoms in Npc2−/− mice through transduction of BECs, and possibly neurons via viral passage across the BBB. Methods Six weeks old Npc2−/− mice were intravenously injected with the AAV-BR1-NPC2 vector. Composite phenotype scores and behavioral tests were assessed for the following 6 weeks and visually documented. Post-mortem analyses included gene expression analyses, verification of neurodegeneration in Purkinje cells, determination of NPC2 transduction in the CNS, assessment of gliosis, quantification of gangliosides, and co-detection of cholesterol with NPC2 in degenerating neurons. Results Treatment with the AAV-BR1-NPC2 vector improved motor functions, reduced neocortical inflammation, and preserved Purkinje cells in most of the mice, referred to as high responders. The vector exerted tropism for BECs and neurons resulting in a widespread NPC2 distribution in the brain with a concomitant reduction of cholesterol in adjacent neurons, presumably not transduced by the vector. Mass spectrometry imaging revealed distinct lipid alterations in the brains of Npc2−/− mice, with increased GM2 and GM3 ganglioside accumulation in the cerebellum and hippocampus. AAV-BR1-NPC2 treatment partially normalized these ganglioside distributions in high responders, including restoration of lipid profiles towards those of Npc2+/+ controls. Conclusion The data suggests cross-correcting gene therapy to the brain via delivery of NPC2 from BECs and neurons.https://doi.org/10.1186/s12987-025-00621-4AAV-BR1Blood–brain barrierViral gene therapyNiemann-Pick type C2 diseaseNPC2Cross-correction |
| spellingShingle | Charlotte Laurfelt Munch Rasmussen Signe Frost Frederiksen Christian Würtz Heegaard Maj Schneider Thomsen Eva Hede Bartosz Laczek Jakob Körbelin Daniel Wüstner Louiza Bohn Thomsen Markus Schwaninger Ole N. Jensen Torben Moos Annette Burkhart Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2 Fluids and Barriers of the CNS AAV-BR1 Blood–brain barrier Viral gene therapy Niemann-Pick type C2 disease NPC2 Cross-correction |
| title | Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2 |
| title_full | Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2 |
| title_fullStr | Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2 |
| title_full_unstemmed | Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2 |
| title_short | Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2 |
| title_sort | endothelial and neuronal engagement by aav br1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of niemann pick type c2 |
| topic | AAV-BR1 Blood–brain barrier Viral gene therapy Niemann-Pick type C2 disease NPC2 Cross-correction |
| url | https://doi.org/10.1186/s12987-025-00621-4 |
| work_keys_str_mv | AT charlottelaurfeltmunchrasmussen endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT signefrostfrederiksen endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT christianwurtzheegaard endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT majschneiderthomsen endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT evahede endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT bartoszlaczek endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT jakobkorbelin endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT danielwustner endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT louizabohnthomsen endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT markusschwaninger endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT olenjensen endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT torbenmoos endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 AT annetteburkhart endothelialandneuronalengagementbyaavbr1genetherapyalleviatesneurologicalsymptomsandlipiddepositioninamousemodelofniemannpicktypec2 |